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Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2-3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase IIβ, but that topoisomerase lia and -β occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase IIβ into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation.

Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2-3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase IIβ, but that topoisomerase IIα and -β occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase IIβ into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation. [PUBLICATION ABSTRACT]

Although high dose n-3 PUFA supplementation reduces exercise- and hyperpnoea-induced bronchoconstriction (EIB/HIB), there are concurrent issues with cost, compliance and gastrointestinal discomfort. It is thus pertinent to establish the efficacy of lower n-3 PUFA doses. Eight male adults with asthma and HIB and eight controls without asthma were randomly supplemented with two n-3 PUFA doses (6·2 g/d (3·7 g EPA and 2·5 g DHA) and 3·1 g/d (1·8 g EPA and 1·3 g DHA)) and a placebo, each for 21 d followed by 14 d washout. A eucapnic voluntary hyperpnoea (EVH) challenge was performed before and after treatments. Outcome measures remained unchanged in the control group. In the HIB group, the peak fall in forced expiratory volume in 1 s (FEV1) after EVH at day 0 (−1005 (sd 520) ml, −30 (sd 18) %) was unchanged after placebo. The peak fall in FEV1 was similarly reduced from day 0 to day 21 of 6·2 g/d n-3 PUFA (−1000 (sd 460) ml, −29 (sd 17) % v. −690 (sd 460) ml, −20 (sd 15) %) and 3·1 g/d n-3 PUFA (−970 (sd 480) ml, −28 (sd 18) % v. −700 (sd 420) ml, −21 (sd 15) %) (P<0·001). Baseline fraction of exhaled nitric oxide was reduced by 24 % (P=0·020) and 31 % (P=0·018) after 6·2 and 3·1 g/d n-3 PUFA, respectively. Peak increases in 9α, 11β PGF2 after EVH were reduced by 65 % (P=0·009) and 56 % (P=0·041) after 6·2 and 3·1 g/d n-3 PUFA, respectively. In conclusion, 3·1 g/d n-3 PUFA supplementation attenuated HIB and markers of airway inflammation to a similar extent as a higher dose. Lower doses of n-3 PUFA thus represent a potentially beneficial adjunct treatment for adults with asthma and EIB.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P  = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P  = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

BackgroundOn World AIDS Day 2021, the UK Government committed £20 million to expand opt-out HIV testing in EDs in extremely high HIV prevalence (>5/1000) areas as part of their commitment to achieve zero new HIV infections, AIDS and HIV-related deaths by 2030. 34 EDs in London, Brighton, Greater Manchester and Blackpool were included. The initiative started in April 2022 and expanded to include hepatitis C (HCV) and hepatitis B (HBV) testing in collaboration with the HCV Elimination programme.MethodsAll adults undergoing blood tests in EDs had BBV testing (4th generation HIV test, HBV surface antigen and HCV antibody with reflex RNA if HCV antibody positive) unless they opted out. An opt-out approach was taken, based on successful pilots, to maximise uptake and minimise impact on ED workload. Testing information was displayed using accessible and translated posters in EDs. HIV/Sexual Health and Hepatology managed all reactive/positive results.ResultsBy March 2023, 33 EDs had implemented HIV testing, 25 HCV and 19 HBV. From April 2022 through March 2023 there were 1,384,378 adult ED attendances with blood tests and 853,015 HIV, 346,041 HBV and 452,284 HCV tests were performed. Median test uptake increased from 51.1% (HIV), 16.3% (HBV), 23.7% (HCV) in April 2022 to 62% (HIV), 57% (HBV) and 62% (HCV) in March 2023.ED opt-out BBV testing identified 2002 people who were newly diagnosed (343 HIV, 1190 HBV, 484 HCV) and 473 who were previously diagnosed but not in care (HIV 209, HBV 156, HCV 108). Initial linkage to care was 339/552 (61%) for HIV (268/343 (78%) for new HIV diagnoses), 329/1346 (24%) for HBV and 292/592 (49%) for HCV.ConclusionsOpt-out BBV testing in EDs has proven extremely effective for making new BBV diagnoses and re-engaging those previously diagnosed but not in care. We found very high rates of HBV. Initial linkage to care is encouraging and is expected to increase over time.

The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations ( P <5 × 10 −8 ) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A ; P =1.4 × 10 −9 ), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations. Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide and genetic susceptibility to the disease is poorly understood. Here, the authors combine data from Japanese, African American and European samples and identify a common variant in VTI1A that increases CRC risk across all populations.

The Cancer Genetic Markers of Susceptibility (CGEMS) initiative has conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls. In Stage 1, we genotyped 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls; in Stage 2, 24,909 SNPs with low p values observed in Stage 1 were analyzed in 4,547 cases and 4,434 controls. In Stage 3 we investigated 21 loci in 4,078 cases and 5,223 controls with low p values from Stage 1 and 2 combined. Two novel loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2, rs11249433, (p=6.74 × 10-10 adjusted genotype test with 2 degrees of freedom) resides in a large block of linkage disequilibrium neighboring NOTCH2 and FCGR1B and is predominantly associated with estrogen receptor-positive breast cancer. A second SNP, rs999737 on chromosome 14q24.1 (p=1.74 × 10−7), localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway, a prior candidate pathway for breast cancer susceptibility. We confirmed previously reported markers on chromosome 2q35, 5q11.2, 5p12, 8q24, 10q26, and 16q12.1. Our results underscore the importance of large-scale replication in the identification of low penetrance breast cancer alleles.